This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The purpose of our proposed work is to conduct four 20-microsecond-long molecular dynamics (MD) simulations of the p38a MAP kinase, in its unbound form (in both the solution and crystalline states) and in complex with the small-molecule inhibitor SB203580. Our hope is (a) to thoroughly sample the protein's conformational dynamics, especially those of its highly flexible activation loop, (b) to resolve an important discrepancy between the extant crystallographic and NMR data, (c) to identify potential new binding sites in the protein that might be exploited for drug design efforts, (d) to establish the causes of the increased dynamics observed experimentally when the SB203580 ligand binds, and finally (e) to mimic the ligand-soaking experiments performed by the crystallographers to examine the diffusion and (hopefully) binding of SB203580 within the crystalline environment. The proposed simulations have been devised with the aim of measuring observables that can be validated against experimental data while at the same time providing fundamentally new information on the conformational behavior of a protein that is both an important drug target and a paradigmatic member of the family of serine/threonine protein kinases.